The present invention relates to 6-alpha- and 6-beta-(aminomethyl)penicillanic acid 1,1-dioxides which are substituted on amino nitrogen with benzyl, hydroxybenzyl, picolyl or phenethyl, pharmaceutically-acceptable salts thereof and conventional esters thereof which are hydrolyzable in vivo. While some of these compounds possess antibacterial activity per se, their principle value is as beta-lactamase inhibitors. Thus they are useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to beta-lactam antibiotics through production of beta-lactamase enzymes. Also encompassed by the present invention are pharmaceutical compositions comprising a present beta-lactamase inhibiting compound and a known beta-lactam antibiotic; and methods of treating bacterial infections with the above pharmaceutical compositions.
Related compounds, viz, penicillanic acid, 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); various 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, U.S. Pat. No. 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S. Pat. No. 4,237,051) have been previously described as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections.
U.K. Patent Application No. 2,053,220, published Feb. 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula ##STR1## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. These definitions, by appropriate selection of R.sub.a, R.sub.b and R.sub.c, may possibly define the simple 6-beta-(aminomethyl)- and 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxides used as intermediates in the preparation of the compounds of the present invention. No specific method for preparation of these intermediate compounds is present in the disclosure of this U.K. application.